An ENU-induced p.C225S missense mutation in the mouse Tgfb1 gene does not cause Camurati-Engelmann disease-like skeletal phenotypes

Camurati-Engelmann disease (CED) is a rare sclerosing bone disorder in humans with autosomal dominant inheritance. Mutations in the gene (TGFB1) that encodes transforming growth factor-β1 (TGF-β1) are causative for CED. TGF-β1 signaling is enhanced by the CED-causing mutations. In this study, we performed Tgfb1 mutation screening in an ENU-mutagenized mouse genomic DNA library. We identified a missense mutation in which cysteine was substituted by serine at position 225 (p.C225S), that corresponded to the CED-causing mutation (p.C225R). TGF-β1 mutant protein carrying p.C225S was secreted normally into the extracellular space. Reporter gene assays showed that the p.C225S mutants enhanced TGF-β signaling at the same level as p.C225R mutants. We generated p.C225S homozygous mice and confirmed that the mature TGF-β1 levels in the culture supernatants of the calvarial cells from the homozygotes were significantly higher than those from wild-type mice. Although the skull and femur are sclerotic in CED, these phenotypes were not observed in p.C225S homozygous mice. These results suggest that human and mouse bone tissue react differently to TGF-β1. These findings are useful to pharmacological studies using mouse models in developing drugs that will target TGF-β signaling.